Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common, dominantly inherited kidney diseases of man. ADPKD is responsible for 10% of all patients requiring chronic dialysis or renal transplant. Currently, 500,000 Americans and 5 million people worldwide are affected with this disorder. Annual healthcare cost is estimated at 1 billion dollars in the U.S. alone. The exact molecular defect of ADPKD is unknown and besides transplantation, no curative treatment exists. This proposal attempts to apply modern molecular biology, and biochemistry to study aberrant gene expression in ADPKD, to produce molecular probes and to define the set of molecular parameters that are specifically altered in ADPKD. Our long term goal is to fully characterize the molecular genetics underlying the defect(s) in ADPKD. With the ADPKD gene characterized, accurate presymptomatic diagnostic tests can be designed. In addition, pharmacological and somatic therapies can be developed to treat and to prevent ADPKD. Specifically we propose to (1) construct and characterize cDNA libraries representative of both normal and polycystic human kidneys, (2) perform detailed parallel kinetic cRNA library hybridization analysis of normal versus ADPKD kidney to establish a reliable upper limit on the number of differentially expressed transcripts, (3) perform parallel library subtractions to isolate and characterize ADPKD specific cDNA clones, (4) characterize the chromosomal locations of clones isolated from (3). Clones that are not located on human chromosome 16 are not likely to be relevant to ADPKD). Clones that are located on chromosome 16 will be characterized futher by cytogenetics and linkage analysis to known ADPKD markers, (5) characterize the tissue distribution of relevant clones, (6) use modern synthetic peptide and antipeptide antibody technologies to identify and characterize protein products represented by selected clones in both cultured cells and tissue sections.